Nanoscale CaO₂‐Loaded Surface‐Engineered Iodine‐125 Seed with Sustained Self‐Oxygenation for Sensitized Tumor Brachytherapy

Abstract Iodine‐125 (¹²⁵I) brachytherapy (BT) is renowned for its precision and effectiveness in delivering localized radiation doses to solid tumors. However, the therapeutic efficacy of traditional¹²⁵I seed is often limited due to the inherent and acquired radioresistance. Based on the importance of tumor hypoxia in radioresistance, a novel “in situ oxygen‐supplement” surface‐modified radioactive ¹²⁵I seed (¹²⁵I@TNT‐CaO₂) is designed and constructed to overcome hypoxia‐induced radioresistance in tumor BT. Titanium dioxide nanotubes (TNTs) are modified on the titanium shell of traditional ¹²⁵I seed and loaded with nanoscale calcium peroxide (CaO₂), further leading to a sustained release of O₂. This in situ oxygen delivery system sensitizes hypoxic tumor regions to ¹²⁵I BT, significantly improving therapeutic efficacy by inducing more ROS generation and DNA damage. Both in vitro and in vivo experiments demonstrate enhanced tumor suppression and apoptosis, with elevated O₂ levels further inhibiting hypoxia‐inducible factor 1‐alpha (HIF‐1α) and its associated signaling pathways. This innovative ¹²⁵I@TNT‐CaO₂ seed presents a promising paradigm to enhance the effectiveness of BT by reversing hypoxia‐mediated resistance.